tbuckley/cabot-search huggingface dataset:
A guide and pragmatic considerations for applying GRADE to network meta-analysis
Authors: Ariel Izcovich, Derek K Chu, Reem A Mustafa, Gordon Guyatt, Romina Brignardello-Petersen
Journal: BMJ (2023)

Assessing the certainty of evidence from network meta-analyses using the GRADE (grading of recommendations, assessment, development, and evaluations) approach requires not only a thorough understanding of the methods but also substantial workload for raters. This article describes how implementing practical strategies (including rule setting and automation) can facilitate efficient application of the GRADE approach to rating certainty of evidence in network meta-analyses while maintaining rigor. This article describes a stepwise strategy for proceeding through the process, including assessment of the certainty of direct, indirect, and NMA estimates; developing directions for each step in the process; implementation of rules to improve robustness of information appraisal to reduce workload; and alternatives for automation of some of the required steps. The presented approach includes a detailed description of every step of the process supported by figures, tables, and real life examples. To facilitate implementation of this process, a spreadsheet that incorporates automation of several of the steps described is also provided (https://www.covid19lnma.com/).
Uncoupling elephant TP53 and cancer
Authors: Fritz Vollrath
Journal: Trends in Ecology & Evolution (2023)

Elephant testicles do not descend, with implications for sperm production being hot enough to compromise germline DNA replication/repair. Uniquely, elephants also possess 20 copies of a gene encoding for the p53 protein. Did elephants evolve multiplication of the TP53 gene complex to protect their germline rather than to fight cancer?
A Review of Recent Progress on Collagen‐Based Biomaterials (Adv. Healthcare Mater. 16/2023)
Authors: Manhui Zheng, Xuechuan Wang, Yining Chen, Ouyang Yue, Zhongxue Bai, Boqiang Cui, Huie Jiang, Xinhua Liu
Journal: Advanced Healthcare Materials (2023)

Collagen-Based Biomaterials Collagen-based biomaterials (CBBs) have been confirmed to prepare dressings and dermal substitutes, surgical sutures, plasma substitutes, tissue-engineered scaffolds, etc. Article 2202042 by Xuechuan Wang, Huie Jiang, Xinhua Liu, and co-workers, provides—in combination with the situation in China—thorough strides in CBBs structures, cross-linking, forming technologies, real-world applications, and the underlying development directions, which are beneficial for the exploration of the development strategy, and international reach of China's collagen industry.
Why I . . . study gastronomy
Authors: Kathy Oxtoby
Journal: BMJ (2023)

delicate, final touches to her three course menu.It starts with a venison shami kebab-in memory of her grandmother's home in Pakistan.The main course is a Kashmiri style sous vide duck breast.The final dish is a saffron, rosewater, and cardamom pannacotta, served with a deconstructed baklava-inspired by her love of the dessert as a child.
The therapeutic potential of natural killer cells in neuropathic pain
Authors: Hyoung Woo Kim, Shuaiwei Wang, Alexander J. Davies, Seog Bae Oh
Journal: Trends in Neurosciences (2023)

Novel disease-modifying treatments for neuropathic pain are urgently required. The cellular immune response to nerve injury represents a promising target for therapeutic development. Recently, the role of natural killer (NK) cells in both CNS and PNS disease has been the subject of growing interest. In this opinion article, we set out the case for NK cell-based intervention as a promising avenue for development in the management of neuropathic pain. We explore the potential cellular and molecular targets of NK cells in the PNS by contrasting with their reported functional roles in CNS diseases, and we suggest strategies for using the beneficial functions of NK cells and immune-based therapeutics in the context of neuropathic pain.
The nucleotide receptor STING translocates to the phagosomes to negatively regulate anti-fungal immunity
Authors: Tian Chen, Yiting Feng, Wanwei Sun, Guimin Zhao, Han Wu, Xiaochen Cheng, Fabao Zhao, Lei Zhang, Yi Zheng, Peng Zhan, Wei Zhao, Bingyu Liu, Chengjiang Gao
Journal: Immunity (2023)
Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion
Authors: Edyta E. Wojtowicz, Jayna J. Mistry, Vladimir Uzun, Charlotte Hellmich, Anita Scoones, Desmond W. Chin, Laura M. Kettyle, Francesca Grasso, Allegra M. Lord, David J. Wright, Graham J. Etherington, Petter S. Woll, Mirjam E. Belderbos, Kristian M. Bowles, Claus Nerlov, Wilfried Haerty, Leonid V. Bystrykh, Sten Eirik W. Jacobsen, Stuart A. Rushworth, Iain C. Macaulay
Journal: Genome biology (2023)

Abstract Background Platelets and erythrocytes constitute over 95% of all hematopoietic stem cell output. However, the clonal dynamics of HSC contribution to these lineages remains largely unexplored. Results We use lentiviral genetic labeling of mouse hematopoietic stem cells to quantify output from all lineages, nucleate, and anucleate, simultaneously linking these with stem and progenitor cell transcriptomic phenotypes using single-cell RNA-sequencing. We observe dynamic shifts of clonal behaviors through time in same-animal peripheral blood and demonstrate that acute platelet depletion shifts the output of multipotent hematopoietic stem cells to the exclusive production of platelets. Additionally, we observe the emergence of new myeloid-biased clones, which support short- and long-term production of blood cells. Conclusions Our approach enables kinetic studies of multi-lineage output in the peripheral blood and transcriptional heterogeneity of individual hematopoietic stem cells. Our results give a unique insight into hematopoietic stem cell reactivation upon platelet depletion and of clonal dynamics in both steady state and under stress.
Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos
Authors: Bieke Bekaert, Annekatrien Boel, Lisa De Witte, Winter Vandenberghe, Mina Popovic, Panagiotis Stamatiadis, Gwenny Cosemans, Lise Tordeurs, Athina-Maria De Loore, Susana Marina Chuva de Sousa Lopes, Petra De Sutter, Dominic Stoop, Paul Coucke, Björn Menten, Björn Heindryckx
Journal: Molecular Therapy (2023)
Genomic characteristics of SARS-CoV-2 variants and their clinical impact on patients with COVID-19 in Taiwan
Authors: Hung-Chieh Su, Zi-Lun Lai, Yu-Chang Chang, Meng-Yu Cheng, Wen-Hsin Hsih, Yi-Jhen Chen, Chia-Huei Chou, Chieh-Lung Chen, Yu-Chao Lin, Tsai-Hsiu Lin, Chiung-Tzu Hsiao, Mao-Wang Ho, Hong-Mo Shih, Po-Ren Hsueh, Der-Yang Cho
Journal: Journal of Infection (2023)
Targeting nonalcoholic fatty liver disease via gut microbiome-centered therapies
Authors: Mijra Koning, Hilde Herrema, Max Nieuwdorp, Abraham S. Meijnikman
Journal: Gut Microbes (2023)

Humans possess abundant amounts of microorganisms, including bacteria, fungi, viruses, and archaea, in their gut. Patients with nonalcoholic fatty liver disease (NAFLD) exhibit alterations in their gut microbiome and an impaired gut barrier function. Preclinical studies emphasize the significance of the gut microbiome in the pathogenesis of NAFLD. In this overview, we explore how adjusting the gut microbiome could serve as an innovative therapeutic strategy for NAFLD. We provide a summary of current information on untargeted techniques such as probiotics and fecal microbiota transplantation, as well as targeted microbiome-focused therapies including engineered bacteria, prebiotics, postbiotics, and phages for the treatment of NAFLD.
Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor–related Apoptosis-inducing Ligand in FGFR3-mutated Tumors
Authors: Clarice S. Groeneveld, Virginia Sanchez-Quiles, Florent Dufour, Mingjun Shi, Florent Dingli, Rémy Nicolle, Elodie Chapeaublanc, Patrick Poullet, Daniel Jeffery, Clémentine Krucker, Pascale Maillé, Francis Vacherot, Dimitri Vordos, Simone Benhamou, Thierry Lebret, Olivier Micheau, Andrei Zinovyev, Damarys Loew, Yves Allory, Aurélien de Reyniès, Isabelle Bernard-Pierrot, François Radvanyi
Journal: European Urology (2023)

Molecular understanding of muscle-invasive (MIBC) and non–muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions. Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial–derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown. Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model. Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant. This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation. We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.
Under-researched populations and topics in sport and exercise medicine (SEM)
Authors: Sharief Hendricks, Natheema Isaacs, Dhavina Naidoo, Lara Paul
Journal: British Journal of Sports Medicine (2023)

In this South African Sports Medicine Association (SASMA) edition of BJSM , we spotlight work on under-researched populations and topics in sport and exercise medicine (SEM). These populations include youth sport, para athletes, women's sport, and trans and gender non-conforming (TGNC) athletes. The topics include lesser-understood concussion risk factors such as personal protective equipment, COVID-19 and how para football players perceive concussion. We also include topics on the internal consistency of mental health tools in youth sport, and the challenges of working in SEM—from undergraduate medical training, forecasts to reduce heat-illness and working as a clinician in women's rugby. The International Festival of Sports, Exercise and Medicine Conference 2022, co-hosted by SASMA, was a great success, with over 450 delegates in attendance. Congratulations to Professor Christa van Rensburg (@ChristaJVR) and the organising committee. The next conference is planned for October 2024, and our international experts are already lined up, so watch this space! Our journal, the South African Journal of Sports Medicine (@SAsportmed) is on Scopus and PubMed. This is a huge step for the journal and SASMA, and we congratulate Professor Mike Lambert (@MikeLambert01) and team for their hard work on taking the journal to new heights. ![Graphic][1]</img> Personal protective equipment to reduce … [1]: /embed/inline-graphic-1.gif
Identification of Lineage-specific Transcriptional Factor–defined Molecular Subtypes in Small Cell Bladder Cancer
Authors: Mingxiao Feng, Andres Matoso, Gabriel Epstein, Megan Fong, Yong Hyun Park, Andrew Gabrielson, Sunil Patel, Bagdan Czerniak, Eva Compérat, Jeannie Hoffman-Censits, Max Kates, Seungchan Kim, David McConkey, Woonyoung Choi
Journal: European Urology (2023)
TREATMENT OF TRIPLE-CLASS REFRACTORY DISEASE: BEYOND IMMUNOTHERAPY
Authors: M. Gavriatopoulou
Journal: HemaSphere (2023)

Proteasome inhibitors (PIs),immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (MoAbs) are the cornerstone of multiple myeloma (MM) therapeutics. After the incorporation of novel agents the clinical outcomes of patients with MM have improved significantly, however prognosis of patients refractory to three drug classes (triple-class refractory [TCR]) is extremely poor. Observational data indicate an overall response rate of approximately 30% and overall survival less than 1 year. Novel agents with different mechanisms of action have been studied and have demonstrated significant activity in TCR MM, including anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cells, anti-BCMA antibody-drug conjugates and exportin 1 (XPO1) inhibitors. Selinexor is a first-in-class, selective exportin-1 inhibitor. Selinexor in combination with dexamethasone has emerged as an important therapeutic approach for heavily pretreated TCR patients with safe and manageable toxicity. Melflufen in combination with dexamethasone was granted accelerated approval by FDA in February 2021 for RRMM in patients who have previously failed at least four lines of therapy. However, examination of OS data from this trial found a higher death rate (48% vs. 43%) in the melflufen group, leading the FDA in October 2021 to withdraw this approval. The drug is approved in the EU. Several other small molecule cereblon E3 ligase modulators (CELMoDs) have been developed for treatment of MM the past few years. This group includes iberdomide (CC-220), which binds to cereblon with an affinity that is twenty times higher than that of either lenalidomide or pomalidomide, leading to more efficient degradation of Ikaros and Aiolos. The combination of iberdomide with dexamethasone in heavily pretreated MM patients yielded ORRs of 26%-32% with serious adverse events noted in 53%. Avadomide (CC-122) is another glutarimide-based cereblon modulator that has broader activity than lenalidomide, possibly due to deeper and faster kinetics of Aiolos degradation. Mezigdomide (CC-92480), another promising drug, showed significant antimyeloma activity in cell lines, including those resistant to pomalidomide and lenalidomide. In addition, venetoclax has demonstrated significant activity in t(11;14) MM patients and represents another therapeutic option. The most appropriate sequencing of existing therapies and the most potent treatment combination still remains unanswered.
The genetics of autism spectrum disorder in an East African familial cohort
Authors: Islam Oguz Tuncay, Darlene DeVries, Ashlesha Gogate, Kiran Kaur, Ashwani Kumar, Chao Xing, Kimberly Goodspeed, Leah Seyoum-Tesfa, Maria H. Chahrour
Journal: Cell Genomics (2023)

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.
Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer
Authors: Yubo Wang, Jian Min, Xiangping Deng, Tian Feng, Hebing Hu, Xinyi Guo, Yan Cheng, Baohua Xie, Yu Yang, Chun-Chi Chen, Rey-Ting Guo, Chune Dong, Hai-Bing Zhou
Journal: Acta Pharmaceutica Sinica B (2023)

Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα+) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα+ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.
Antiretroviral Therapy during Pregnancy and the Risk of an Adverse Outcome
Authors: Ruth E. Tuomala, David E. Shapiro, Lynne M. Mofenson, Yvonne Bryson, Mary Culnane, Michael D. Hughes, M.J. O'Sullivan, Gwendolyn Scott, Alice M. Stek, Diane Wara, Marc Bulterys
Journal: New England Journal of Medicine (2002)

Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy.
Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study
Authors: Vicky Brocklebank, Patrick R. Walsh, Kate Smith-Jackson, Thomas M. Hallam, Kevin J. Marchbank, Valerie Wilson, Theophile Bigirumurame, Tina Dutt, Emma K. Montgomery, Michal Malina, Edwin K. S. Wong, Sally Johnson, Neil S. Sheerin, David Kavanagh
Journal: Blood (2023)

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.
IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion
Authors: Fabian M. P. Kaiser, Iga Janowska, Roberta Menafra, Melanie de Gier, Jakov Korzhenevich, Ingrid Pico-Knijnenburg, Indu Khatri, Ansgar Schulz, Taco W. Kuijpers, Arjan C. Lankester, Lukas Konstantinidis, Miriam Erlacher, Susan Kloet, Pauline A. van Schouwenburg, Marta Rizzi, Mirjam van der Burg
Journal: Blood (2023)

Although absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations in the IL-7 receptor α chain (IL-7Rα) still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples from healthy controls and patients who are IL-7Rα deficient, in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7R signaling plays a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors but not of pre-BII large cells and has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate the specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of patients with IL-7Rα deficiency still expressed myeloid-specific genes. Collectively, our results unveil a previously unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7R signaling in leukemogenesis.